CN113712938A - V-9302 nano-particles for treating psoriasis and preparation method thereof - Google Patents
V-9302 nano-particles for treating psoriasis and preparation method thereof Download PDFInfo
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Abstract
The invention provides V-9302 nano-particles for treating psoriasis and a preparation method thereof. The V-9302 nanoparticles comprise biological particles of HaCAT cell origin and V-9302; the invention also discloses a preparation method of the V-9302 nano-particles, which comprises the steps of firstly treating the HaCAT cells under the ultraviolet condition, then extruding the HaCAT cells and the V-9302 under the blending condition, collecting an extrusion liquid, centrifuging 10,000g, discarding the precipitate, centrifuging the supernatant at 150,000g for 120 minutes, collecting the precipitate, and re-suspending to obtain the V-9302 nano-particles. The V-9302 nano-particles prepared by the invention can be used for treating psoriasis, and the V-9302 nano-particles have narrower particle size distribution, better drug encapsulation efficiency and good biocompatibility.
Description
Technical Field
The invention belongs to the technical field of nano-drug carriers, and particularly relates to V-9302 nano-particles for treating psoriasis and a preparation method thereof.
Background
Psoriasis is commonly called as psoriasis, is a chronic inflammatory skin disease, has long course of disease and easy recurrence tendency, and some cases are not cured almost for the whole life. The disease is mainly developed in young and old years, and has great influence on the physical health and mental conditions of patients. The clinical manifestations are erythema and scale, the disease can be developed on the whole body, the scalp and the limb extension are common, and 2-3% of the population is deeply afflicted by the disease. Almost 800 million psoriasis patients exist in China alone. The external treatment of psoriasis mainly comprises glucocorticoid and vitamin D3 derivatives. Among them, glucocorticoids have quick and good effects, but have the disadvantage of being easy to repeat, and patients usually do not receive hormone treatment psychologically because of worrying about side effects; vitamin D3 drugs represented by calcipotriol are first-line drugs for treating psoriasis at present, are 'gold standards' of non-hormone external drugs, but some patients have local stimulation and have the problem of influencing calcium and phosphorus metabolism. Therefore, therapeutic strategies directed to the mechanism of psoriasis development are proposed, and the development of new therapeutic drugs to improve the treatment of the disease is imminent.
V-9302 is a competitive antagonist of transmembrane glutamine transporters and can regulate cellular glutamine uptake. It has been reported that V-9302 can modulate glutamine metabolism in interfering with tumor cells through transporter inhibition. Many tumor cells exhibit a strong glutamine metabolism dependence, making them exhibit uptake of large amounts of glutamine. V-9302 can achieve a certain antitumor effect by interfering with the supply of glutamine. However, there is currently no report of the direct application of V-9302 to the treatment of psoriasis.
How to deliver drugs is also a difficulty in psoriasis treatment. The traditional psoriasis treatment is mainly ointment, gel and the like. Compared with the traditional medicine preparation, the nano-drug carrier has obvious advantages in the aspects of delivering the drug to the epidermis and the dermis, improving the drug concentration of the treatment part and reducing the toxic and side effects of the whole body. The nano-particles have the advantages of smaller particle size, functional diversity and the like, so that the solubility of insoluble drugs is improved, and the capability of the drugs for penetrating compact skin is improved. At present, no related report of V-9302 encapsulated by nanoparticles exists. The V-9302 nano-particles are expected to utilize the pharmacological activity of V-9302 and the delivery characteristics of nano-drugs, improve the drug delivery efficiency and synergistically play the role of resisting psoriasis, and are expected to lay a solid foundation for the development of psoriasis drugs.
Disclosure of Invention
In order to solve the problems in the background art, the invention provides V-9302 nano-particles for treating psoriasis and a preparation method thereof, and provides a new application of V-9302. The V-9302 nano-particles prepared by the invention have narrower particle size distribution, better drug encapsulation efficiency and good biocompatibility. The V-9302 nanoparticles prepared by the invention can be used for treating psoriasis, and are particularly characterized in that the psoriasis-like skin condition is improved, the epidermal layer thickening of the psoriasis-like skin is inhibited, the lesion ear thickening is inhibited, and the IL-23 and IL-17 levels in the psoriasis-like skin are reduced.
The technical scheme adopted by the invention is as follows:
v-9302 nano-particles
The V-9302 nanoparticles are mainly prepared from biological particles of HaCAT cell origin and V-9302.
The V-9302 is a competitive antagonist of transmembrane glutamine flux and has the chemical structural formula:
the particle size of the V-9302 nano-particles is between 120 and 250 nm.
Preparation method of V-9302 nanoparticles
The method comprises the following steps:
1) irradiating HaCAT cells under the condition of ultraviolet light;
2) scraping HaCAT cells with cell, adding V-9302 solution, and resuspending to obtain 5 × 106～8×106cell/mL of cell suspension;
3) the cell suspension passes through an extruder with 10 μm, 2 μm, 1 μm and 0.45 μm filter membranes in sequence;
4) collecting the cell filtrate filtered by the extruder in the step 3, centrifuging, removing the precipitate, and taking supernatant;
5) and (3) continuously centrifuging the supernatant, collecting and drying the precipitate to obtain the V-9302 nanoparticles, or collecting and resuspending the precipitate by a pbs buffer solution to obtain the V-9302 nanoparticles dispersed in the liquid.
The ultraviolet light condition in the step 1) is that the ultraviolet light intensity is 140-200 mu W/cm2The irradiation time is 45-120 min.
The V-9302 solution added in the step 2) contains solvent ethanol with the mass ratio of 10-30%.
In the step 4), the relative centrifugal force during centrifugation is 10,000g, and the centrifugation time is 10 minutes; in the step 5), the relative centrifugal force during centrifugation is 150,000g, and the centrifugation time is 120 minutes.
Application of V-9302 nano-particles in preparing medicine for treating psoriasis
The dosage forms of the medicine comprise powder, injection, capsules, tablets and oral liquid.
The invention has the beneficial effects that:
the V-9302 nano-particles prepared by the invention have solubilization and stabilization effects on the medicine, and improve the skin permeability and retention by utilizing the nano effect and the ethosome-like effect, thereby improving the intake of effective treatment substances at pathological change positions and being beneficial to improving the medicine utilization rate and the effective rate.
The whole preparation process is simple to operate, stable in condition and good in reproducibility. A large number of experiments show that the V-9302 nano-particles have good effect on treating psoriasis, no toxic or side effect and low cost. The method is favorable for delaying the progress and deterioration of the disease, and has the advantages of strong operability, capability of obviously reducing the diagnosis and treatment cost of patients and medical institutions and the like.
Detailed Description
The present invention will be further described with reference to the following examples.
Example 1 preparation and characterization of V-9302 nanoparticles
According to the prescription and the preparation point of each group of V-9302 nano-particles in the table 1, the preparation method comprises the following steps:
inoculating the cells into a culture dish of 10cm, and carrying out ultraviolet condition treatment when the cell coverage rate reaches 80-90%. After further culturing for 2h, the cells were collected by scraping with a spatula, and resuspended by adding 400. mu.g/mL of a drug solution to obtain 5X 106～8×106cells/mL cell suspension. The cell suspension was passed sequentially through 10. mu.M, 2. mu.M, 1. mu.M, 0.45. mu.M filters using a micro-extruder, each size being repeated 2 times. The cell filtrate was collected and centrifuged (10,000g, 10min) to discard the pellet and to take the supernatant. Centrifuging the supernatant (150,000g for 120 min), and collecting the precipitate to obtain V-9302 nanoparticles
And (3) after the obtained V-9302 nanoparticles are resuspended by PBS, observing whether the V-9302 nanoparticles dispersed in the liquid have the Tyndall effect or not and detecting the average size of the nanoparticles by dynamic light scattering.
TABLE 1 formulation and preparation points of V-9302 nanoparticles
Example 2 characterization of V-9302 nanoparticles
Taking each group of V-9302 nano-particles prepared in example 1, determining the content of V-9302 in the nano-particles by a high-phase liquid-phase method, and calculating the encapsulation efficiency according to the following formula: encapsulation ratio (%) ═ V-9302 mass (mg) in nanoparticles/drug dose (mg). Drug entrapment is one of the key factors in the preparation of nano-drug formulations. The drug encapsulation efficiency in each nanoparticle is shown in table 2. The result shows that the drug encapsulation efficiency is kept at about 24-36% within the prescription range and the process parameter variation, and the preparation process is reasonable.
TABLE 2 encapsulation efficiency of V-9302 nanoparticles
| Group of | Encapsulation efficiency (%) |
| 1 | 29.8 |
| 2 | 24.2 |
| 3 | 32.4 |
| 4 | 35.7 |
| 5 | 27.6 |
| 6 | 26.8 |
| 7 | 27.1 |
| 8 | 28.9 |
| 9 | 28.3 |
| 10 | 30.4 |
| 11 | - |
| 12 | 18.7 |
| 13 | - |
| 14 | 15.7 |
Example 3 therapeutic Effect of V-9302 nanoparticles on psoriasis
3.1) establishment of psoriasis mouse model
BALB/c mice are taken as animal models, adaptive feeding is carried out for 1 week before experiments, and fasting is carried out for 12 hours before model building without water supply. After shaving the backs of mice in an experimental group, fixing and selecting a skin area of 2cm multiplied by 3cm, smearing 5% of imiquimod cream (60.5 mg/mouse/day) on a back depilation area every day, smearing 5% of imiquimod cream (1 mg/mouse/day) on an ear depilation area every day, continuously using the medicine for 10 days, successfully modeling by taking scales and red spots appearing on the back skin of the mice as model building, and using the normal control group mice to dose vaseline with the same dosage every day, and building a module by using the method.
Mice after successful modeling were randomly divided, and each sample group prepared in example 1 was applied to the skin of psoriasis, and administered daily for 10 days. Normal control mice were given an equivalent dose of PBS.
In the experiment, the severity of psoriasis skin of each group of mice is evaluated by a blind method by referring to the clinical PASI scoring standard. The scoring included erythema, scaling and thickening. The scoring criteria were as follows: 0: no phenomenon occurs; 1: slightly; 2: moderate; 3: is remarkable; 4, the ratio is very obvious. And the thickness of the mouse ear was measured with an electronic vernier caliper.
10 days after administration, the mice were sacrificed and a portion of the dorsal skin was taken for enzyme-linked immunosorbent assay (ELISA) detection. Taking a proper amount of skin tissue, adding PBS, fully mixing, preparing tissue homogenate, centrifuging (1000g for 10min), taking supernatant, and detecting the content of IL-23 and IL-17 in the skin of each group according to the operation of a kit.
3.2) Experimental groups
Normal control group: vaseline for molding and PBS with the same dosage as the nano particles
Model group: PBS with the same dosage as the nano-particles after the molding is successful
Administration intervention group 1: after the molding is successful, the skin surface of the nanoparticles of the group of example 1 is continuously dosed for 10 days;
administration intervention group 2: after the molding is successful, the skin surface of the nanoparticles of the group of example 2 is continuously dosed for 10 days;
administration intervention group 3: after the molding is successful, the skin surface of the nanoparticles of the group of example 3 is continuously dosed for 10 days;
administration intervention group 4: after the molding is successful, the skin surface of the nanoparticles of the example 4 group is continuously administrated for 10 days;
administration intervention group 5: after the molding is successful, the skin surface of the nanoparticles of the example 5 group is continuously administrated for 10 days;
administration intervention group 6: after the molding is successful, the skin surface of the nanoparticles of the example 6 group is continuously administrated for 10 days;
administration intervention group 7: after the molding is successful, the skin surface of the nanoparticles of the example 7 group is continuously administrated for 10 days;
administration intervention group 8: after the molding is successful, the skin surface of the nanoparticles of the example 8 group is continuously administrated for 10 days;
administration intervention group 9: after the molding is successful, the skin surface of the nanoparticles of the example 9 group is continuously administrated for 10 days;
administration intervention group 10: after the molding is successful, the skin surface of the nanoparticles of the example 10 group is continuously dosed for 10 days;
administration intervention group 11: after the molding is successful, the skin surface of the nanoparticles of the example 11 group is continuously administrated for 10 days;
administration intervention group 12: after the molding is successful, the skin surface of the nanoparticles of the example 12 group is continuously administrated for 10 days;
administration intervention group 14: after the molding is successful, the skin surface of the nanoparticles of the example 14 group is continuously administrated for 10 days;
administration intervention group 15: after the model is successfully made, continuously administering the V-9302 solution on the skin surface for 10 days;
administration intervention group 16: after successful modeling, the V-9302 solution + nanoparticles of example 11 set (separated by 1 hour) were continuously administered to the skin surface for 10 days
3.3) results and conclusions of the experiment
TABLE 3 results of V-9302 nanoparticle treatment of psoriatic rats
The results of the experiment are shown in table 3. Under the reasonable prescription and preparation process conditions, the clinical PASI scoring standard of the V-9302 nano-particles is obviously better than that of other administration intervention groups in three aspects of erythema, thickness and scale. In addition, the level of IL-23 and IL-17 factors is also significantly inhibited.
The results show that the V-9302 nano-particles can obviously inhibit the problems of erythema, skin thickening and scaling at the psoriasis lesion part and reduce the levels of key factors IL-23 and IL-17. The medicine prepared by the V-9302 nano-particles and the preparation process parameters have key effects on the anti-psoriasis effect by selecting proper cells and proper ultraviolet condition treatment.
The results show that the V-9302 nanoparticles can effectively promote the improvement of the psoriasis-like skin condition, inhibit the thickening of the epidermis layer of the psoriasis-like skin and the thickening of the pathological ears, and reduce the levels of IL-23 and IL-17 in the psoriasis-like skin, thereby prompting the improvement of the occurrence and the development of the psoriasis. Therefore, the V-9302 nano-particles are expected to be applied to the preparation of psoriasis medicines.
While the invention has been described in connection with what is presently considered to be the most practical and preferred embodiment, it is to be understood that the invention is not to be limited to the disclosed embodiment, but on the contrary, is intended to cover various modifications and equivalent arrangements included within the spirit and scope of the appended claims.
Claims (8)
1. V-9302 nanoparticles, characterized in that the V-9302 nanoparticles are mainly prepared from biological particles of HaCAT cell origin and V-9302.
2. The V-9302 nanoparticle of claim 1, wherein the V-9302 is a competitive antagonist of transmembrane glutamine flux and has the chemical structure:
3. the V-9302 nanoparticles of claim 1, wherein the V-9302 nanoparticles have a particle size of between 120 and 250 nm.
4. The method for preparing V-9302 nanoparticles according to any of claims 1-3, characterized by comprising the following steps:
1) irradiating HaCAT cells under the condition of ultraviolet light;
2) scraping HaCAT cells with cell, adding V-9302 solution, and resuspending to obtain 5 × 106～8×106cell/mL of cell suspension;
3) the cell suspension passes through an extruder with 10 μm, 2 μm, 1 μm and 0.45 μm filter membranes in sequence;
4) collecting the cell filtrate filtered by the extruder in the step 3), centrifuging, removing the precipitate, and taking supernatant;
5) and (3) continuously centrifuging the supernatant, collecting and drying the precipitate to obtain the V-9302 nano-particles, or collecting and resuspending the precipitate to obtain the V-9302 nano-particles dispersed in the liquid.
5. The method of claim 4, wherein the V-9302 nanoparticles are prepared byThe ultraviolet light condition in the step 1) is that the ultraviolet light intensity is 140-200 mu W/cm2The irradiation time is 45-120 min.
6. The method for preparing V-9302 nanoparticles according to claim 4, characterized in that the V-9302 solution added in the step 2) contains 10-30% by mass of ethanol as a solvent.
7. The method for preparing V-9302 nanoparticles according to claim 4, wherein in the step 4), the relative centrifugal force is 10,000g and the centrifugal time is 10 minutes; in the step 5), the relative centrifugal force during centrifugation is 150,000g, and the centrifugation time is 120 minutes.
8. Use of the V-9302 nanoparticles according to any one of claims 1 to 3, in the preparation of a medicament for the treatment of psoriasis, wherein the medicament is in a form selected from the group consisting of a powder, an injection, a capsule, a tablet, and an oral liquid.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20200095190A1 (en) * | 2016-12-09 | 2020-03-26 | Vanderbilt University | Glutamine Transport Inhibitors and Methods for Treating Cancer |
| CN111643669A (en) * | 2020-06-30 | 2020-09-11 | 广东省中医院（广州中医药大学第二附属医院、广州中医药大学第二临床医学院、广东省中医药科学院） | Application of glutaminase inhibitor in preparation of medicine for treating psoriasis |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20200095190A1 (en) * | 2016-12-09 | 2020-03-26 | Vanderbilt University | Glutamine Transport Inhibitors and Methods for Treating Cancer |
| CN111643669A (en) * | 2020-06-30 | 2020-09-11 | 广东省中医院（广州中医药大学第二附属医院、广州中医药大学第二临床医学院、广东省中医药科学院） | Application of glutaminase inhibitor in preparation of medicine for treating psoriasis |
Non-Patent Citations (1)
| Title |
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| DANAY CIBRIAN ETAL.: "Metabolic Pathways That Control Skin Homeostasis and Inflammation", 《TRENDS IN MOLECULAR MEDICINE》 * |
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